The aims of this project are: 1. To develop a safe and effective polynucleotide dengue vaccine that induces an effective immune response to all four serotypes of dengue virus. 2. Improve a painless electric field based delivery system for the vaccine. 3. Test feasibility of the vaccine through pre-clinical animal studies and phase I/Il human trials. Dengue is an emerging disease that affects tens of millions of individuals each year. It has become a global pandemic since the end of WW II. The last two decades have seen an especially large increase in the number of cases worldwide. During this time, the Americas have seen the emergence of the most severe form of dengue, dengue hemorrhagic fever. In endemic areas, such as Southeast Asia, it is a disease of children and is a common cause of morbidity and mortality in children. Vaccines to dengue viruses have been a goal for most of the 20th century. This project is the development of a vaccine based upon the delivery of a dengue virus polynucleotide vaccine using a painless vaccine delivery system. The vaccine delivery system uses pulsed electric fields to achieve the painless delivery of polynucleotides to the skin of vaccine recipients. Three sets of vaccine constructs, developed at the Walter Reed Army Institute of Research and The Naval Medical Research Center, Silver Spring, MD, will be tested in mice and primates. The vaccines will be delivered using the new delivery system. Immune responses will be measured and resistance to challenge by wild type virus will be assessed. All development will be done using a dengue 2 construct until a candidate formulation is selected. A successful dengue 2 candidate will be tested in human trials. After selection of a candidate formulation, the dengue 1,3 and 4 constructs will be prepared and tested in the animal models. Upon completion of animal studies, human clinical trials will be done using the individual dengue IA candidate vaccines. A separate clinical trial will be done to test a tetravalent formulation. Certified challenge viruses are being developed at WRAIR. These viruses will be used to challenge immune volunteers to assess the ability of vaccines to resist infection by the dengue viruses.